scholarly journals Impairment of Inhibitory Synaptic Transmission in Mice Lacking Synapsin I

1999 ◽  
Vol 145 (5) ◽  
pp. 1039-1048 ◽  
Author(s):  
Sumio Terada ◽  
Tetsuhiro Tsujimoto ◽  
Yosuke Takei ◽  
Tomoyuki Takahashi ◽  
Nobutaka Hirokawa
Keyword(s):  
Synaptic Transmission ◽  
Synaptic Vesicles ◽  
Late Onset ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Epileptic Seizures ◽  
Mutant Mice ◽  
Inhibitory Synapses ◽  
Synapsin I ◽  
Hypertonic Solution

Deletion of the synapsin I genes, encoding one of the major groups of proteins on synaptic vesicles, in mice causes late onset epileptic seizures and enhanced experimental temporal lobe epilepsy. However, mice lacking synapsin I maintain normal excitatory synaptic transmission and modulation but for an enhancement of paired-pulse facilitation. To elucidate the cellular basis for epilepsy in mutants, we examined whether the inhibitory synapses in the hippocampus from mutant mice are intact by electrophysiological and morphological means. In the cultured hippocampal synapses from mutant mice, repeated application of a hypertonic solution significantly suppressed the subsequent transmitter release, associated with an accelerated vesicle replenishing time at the inhibitory synapses, compared with the excitatory synapses. In the mutants, morphologically identifiable synaptic vesicles failed to accumulate after application of a hypertonic solution at the inhibitory preterminals but not at the excitatory preterminals. In the CA3 pyramidal cells in hippocampal slices from mutant mice, inhibitory postsynaptic currents evoked by direct electrical stimulation of the interneuron in the striatum oriens were characterized by reduced quantal content compared with those in wild type. We conclude that synapsin I contributes to the anchoring of synaptic vesicles, thereby minimizing transmitter depletion at the inhibitory synapses. This may explain, at least in part, the epileptic seizures occurring in the synapsin I mutant mice.

Electrophysiological evidence from glutamate microapplications for local excitatory circuits in the CA1 area of rat hippocampal slices

1988 ◽  
Vol 59 (1) ◽  
pp. 110-123 ◽  
Author(s):  
E. P. Christian ◽  
F. E. Dudek
Keyword(s):  
Hippocampal Neurons ◽  
Hippocampal Slices ◽  
Pyramidal Cells ◽  
Inhibitory Synapses ◽  
Excitatory Synapses ◽  
Recording Site ◽  
Postsynaptic Potentials ◽  
Inhibitory Postsynaptic Potentials ◽  
Ca1 Area ◽  
Transverse Slice

1. Evidence for local excitatory synaptic connections in CA1 of the rat hippocampus was obtained by recording excitatory postsynaptic potentials (EPSPs) intracellularly from pyramidal cells during local microapplications of glutamate. 2. Experiments were performed in hippocampal slices cut parallel to (transverse slice) or perpendicular to (longitudinal slice) alvear fibers. In normal solutions, glutamate microdrops (10–20 mM, 10–20 micron diam) applied in CA1 within 400 micron of recorded cells sometimes increased the frequency of inhibitory postsynaptic potentials for 5–10 s in both transverse and longitudinal slices. Increases in EPSP frequency were also occasionally observed, but only in transverse slices. Tetrodotoxin (1 microgram/ml) blocked glutamate-induced increases in PSP frequency, thus indicating that they were not caused by subthreshold effects on presynaptic terminals. Increases in PSP frequency were interpreted to result from glutamate activation of hippocampal neurons with inhibitory and excitatory connections to recorded neurons. 3. In both slice orientations, local excitatory circuits were studied in more isolated conditions by surgically separating CA1 from CA3 (transverse slices) and by blocking GABAergic inhibitory synapses with picrotoxin (5–10 microM). Microdrops were systematically applied at 200 and 400 micron on each side of the recording site. Significant glutamate-induced increases in EPSP frequency were observed in neurons from both slice orientations to microdrops in at least one of the locations. This provided evidence that excitatory synapses are present in both transverse and longitudinal slices. 4. Substantial increases in EPSP frequency only occurred in neurons from longitudinal slices when glutamate was microapplied 200 micron or less from the recording site. In transverse slices, however, large increases in EPSP frequency were observed to glutamate microapplications at 200 or 400 micron. These data suggest that CA1 local excitatory connections project for longer distances in the transverse than in the longitudinal plane of section. 5. Increases in EPSP frequency, averaged across cells, did not differ significantly in the four microapplication sites in either transverse or longitudinal slices. Thus local excitation in CA1 does not appear to be asymmetrically arranged in the way suggested for CA3. 6. The densities of local excitatory circuits in CA1 versus CA3 were studied by quantitatively comparing glutamate-induced increases in EPSP frequency.(ABSTRACT TRUNCATED AT 400 WORDS)

Enhanced NMDAR-dependent epileptiform activity is controlled by oxidizing agents in a chronic model of temporal lobe epilepsy

1996 ◽  
Vol 76 (6) ◽  
pp. 4185-4189 ◽  
Author(s):  
J. C. Hirsch ◽  
O. Quesada ◽  
M. Esclapez ◽  
H. Gozlan ◽  
Y. Ben-Ari ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Ex Vivo ◽  
Epileptiform Activity ◽  
Hippocampal Slices ◽  
Nmda Antagonist ◽  
Pyramidal Cells ◽  
Resting Membrane Potential ◽  
Postsynaptic Potentials ◽  
Epileptiform Discharges ◽  
Late Part

1. Graded N-methyl-D-aspartate receptor (NMDAR)-dependent epileptiform discharges were recorded from ex vivo hippocampal slices obtained from rats injected a week earlier with an intracerebroventricular dose of kainic acid. Intracellular recordings from pyramidal cells of the CA1 area showed that glutamate NMDAR actively participated in synaptic transmission, even at resting membrane potential. When NMDAR were pharmacologically isolated, graded burst discharges could still be evoked. 2. The oxidizing reagent 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB, 200 microM, 15 min) suppressed the late part of the epileptiform burst that did not recover after wash but could be reinstated by the reducing agent tris (2-carboxyethyl) phosphine (TCEP, 200 microM, 15 min) and again abolished with the NMDA antagonist D-2-amino-5-phosphonovaleric acid (D-APV). 3. Pharmacologically isolated NMDAR-mediated responses were decreased by DTNB (56 +/- 10%, mean +/- SD, n = 6), an effect reversed by TCEP. 4. When only the fast glutamateric synaptic component was blocked, NMDA-dependent excitatory postsynaptic potentials (EPSPs) could be evoked despite the presence of underlying fast and slow inhibitory postsynaptic potentials (IPSPs). DTNB decreased EPSPs to 48 +/- 12% (n = 5) of control. 5. Since a decrease of the NMDAR-mediated response by +/- 50% is sufficient to suppress the late part of the burst, we suggest that epileptiform activity can be controlled by manipulation of the redox sites of NMDAR. Our observations raise the possibility of developing new anticonvulsant drugs that would spare alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-R (AMPAR)-mediated synaptic responses and decrease NMDAR-mediated synaptic transmission without blocking it completely.

Lack of AMPA Receptor Desensitization During Basal Synaptic Transmission in the Hippocampal Slice

1999 ◽  
Vol 81 (6) ◽  
pp. 3096-3099 ◽  
Author(s):  
Gregory O. Hjelmstad ◽  
John T. R. Isaac ◽  
Roger A. Nicoll ◽  
Robert C. Malenka
Keyword(s):  
Synaptic Transmission ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Hippocampal Slice ◽  
Hippocampal Slices ◽  
Release Site ◽  
Pyramidal Cells ◽  
Receptor Desensitization ◽  
Synaptic Receptors ◽  
Basal Synaptic Transmission

Lack of AMPA receptor desensitization during basal synaptic transmission in the hippocampal slice. Excitatory postsynaptic currents in the CA1 region of rat hippocampal slices are mediated primarily by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in response to synaptically released glutamate. Outside-out patches from pyramidal cells in this region have shown that AMPA receptors are desensitized by short (1 ms) pulses of glutamate. We have taken a number of approaches to ask whether synaptic receptors desensitize in response to synaptically released glutamate in the slice. Recordings with paired pulses and minimal stimulation conditions that are presumably activating only a single release site do not show evidence for desensitization. Furthermore, cyclothiazide, a drug that blocks desensitization, does not alter paired-pulse ratios even under conditions of high probability of release, which should maximize desensitization. These results suggest that synaptic receptors do not desensitize in response to synaptically released glutamate during basal synaptic transmission.

scholarly journals ALLN rescues an in vitro excitatory synaptic transmission deficit in Lis1 mutant mice

2013 ◽  
Vol 109 (2) ◽  
pp. 429-436 ◽  
Author(s):  
Joy Y. Sebe ◽  
Marina Bershteyn ◽  
Shinji Hirotsune ◽  
Anthony Wynshaw-Boris ◽  
Scott C. Baraban
Keyword(s):  
Synaptic Transmission ◽  
Neuronal Migration ◽  
Therapeutic Potential ◽  
Hippocampal Slices ◽  
In Utero ◽  
Mutant Mice ◽  
Excitatory Synaptic Transmission ◽  
Calpain Inhibitor ◽  
Tissue Slices ◽  
Littermate Control

LIS1 gene mutations lead to a rare neurological disorder, classical lissencephaly, characterized by brain malformations, mental retardation, seizures, and premature death. Mice heterozygous for Lis1 ( Lis1+/−) exhibit cortical malformations, defects in neuronal migration, increased glutamate-mediated synaptic transmission, and spontaneous electrographic seizures. Recent work demonstrated that in utero treatment of Lis1+/− mutant dams with ALLN, a calpain inhibitor, partially rescues neuronal migration defects in the offspring. Given the challenges of in utero drug administration, we examined the therapeutic potential of ALLN on postnatal lissencephalic cells. Voltage- and current-clamp studies were performed with acute hippocampal slices obtained from Lis1 mutant mice and age-matched littermate control mice. Specifically, we determined whether postnatal ALLN treatment can reverse excitatory synaptic transmission deficits, namely, an increase in spontaneous and miniature excitatory postsynaptic current (EPSC) frequency, on CA1 pyramidal neurons observed in tissue slices from Lis1+/− mice. We found that acute application of ALLN restored spontaneous and miniature EPSC frequencies to wild-type levels without affecting inhibitory postsynaptic synaptic current. Furthermore, Western blot analysis of protein expression, including proteins involved in excitatory synaptic transmission, demonstrated that ALLN blocks the cleavage of the calpain substrate αII-spectrin but does not rescue Lis1 protein levels in Lis1+/− mutants.

scholarly journals Autoantibodies to synapsin I sequestrate synapsin I and alter synaptic function

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Anna Rocchi ◽  
Silvio Sacchetti ◽  
Antonio De Fusco ◽  
Silvia Giovedi ◽  
Barbara Parisi ◽  
...  
Keyword(s):  
Synaptic Vesicles ◽  
Hippocampal Neurons ◽  
Neurological Diseases ◽  
Synaptic Function ◽  
Inhibitory Synapses ◽  
Synapsin I ◽  
Loss Of Function ◽  
Reduced Density ◽  
Cytoplasmic Side

AbstractSynapsin I is a phosphoprotein that coats the cytoplasmic side of synaptic vesicles and regulates their trafficking within nerve terminals. Autoantibodies against Syn I have been described in sera and cerebrospinal fluids of patients with numerous neurological diseases, including limbic encephalitis and clinically isolated syndrome; however, the effects and fate of autoantibodies in neurons are still unexplored. We found that in vitro exposure of primary hippocampal neurons to patient’s autoantibodies to SynI decreased the density of excitatory and inhibitory synapses and impaired both glutamatergic and GABAergic synaptic transmission. These effects were reproduced with a purified SynI antibody and completely absent in SynI knockout neurons. Autoantibodies to SynI are internalized by FcγII/III-mediated endocytosis, interact with endogenous SynI, and promote its sequestration and intracellular aggregation. Neurons exposed to human autoantibodies to SynI display a reduced density of SVs, mimicking the SynI loss-of-function phenotype. Our data indicate that autoantibodies to intracellular antigens such as SynI can reach and inactivate their targets and suggest that an antibody-mediated synaptic dysfunction may contribute to the evolution and progression of autoimmune-mediated neurological diseases positive for SynI autoantibodies.

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